Seung-Jung Park, MD, PhDon behalf of the ZEST investigators

Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent versus

Sirolimus-Eluting Stent and PacliTaxel-Eluting Stent for Coronary Lesions:

The ZEST TrialThe ZEST Trial

Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent versus

Sirolimus-Eluting Stent and PacliTaxel-Eluting Stent for Coronary Lesions:

The ZEST TrialThe ZEST Trial

ZEST Trial– Disclosure Information

ZEST Trial– Disclosure Information

Supported by research grants from

• CardioVascular Research Foundation (CVRF), Seoul, Korea

• Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea (0412-CR02-0704-0001) &

• Medtronic Vascular

• Several clinical trials have documented that sirolimus-eluting

stent (SES; Cypher) and paclitaxel-eluting stent (PES;

Taxus) significantly reduce angiographic restenosis and

repeat revascularization as compared to bare metal stents.

• However, the safety of the first-generation 2 drug-eluting

stents (DES) (sirolimus- and paclitaxel-) has been

concerned by numerous reports of increased late stent

thrombosis, myocardial infarction, and death, especially in

routine clinical practice.

Background

• Zotarolimus-eluting stent (ZES; Endeavor) is a second-

generation DES comprising 3 components: (1) a low-

profile, thin-strut, cobalt-alloy stent; (2) a biocompatible

phosphorylcholine polymer; and (3) zotarolimus, an

antiproliferative drug.

• Although second-generation DES, which may be

theoretically less prone to thrombosis, is currently available,

large randomized trial comparing first vs. second-

generation DES in all-comer settings have been limited.

Background

• To establish the safety and effectiveness of coronary

stenting with zotarolimus-eluting stent (Endeavor,

Medtronic) as compared with sirolimus-eluting stent

(Cypher, Cordis Johnson & Johnson) and paclitaxel-

eluting stent (Taxus, Boston Scientific) in a multicenter,

randomized clinical trial for unselected patients in the

real world.

Objective

Study DesignStudy DesignIntention-to-Treat Analyses

All Comer requiring PCI with DES for coronary lesions All Comer requiring PCI with DES for coronary lesions in 19 Centers of Koreain 19 Centers of Korea(Total 2,640 patients)

Randomize 1:1:1Randomize 1:1:1stratified by 1) Sites, 2) Diabetes, 3) Long lesions (≥ 28 mm) stratified by 1) Sites, 2) Diabetes, 3) Long lesions (≥ 28 mm)

ENDEAVOR®

(N=880)(N=880)

Clinical follow-up at 12 months Clinical follow-up at 12 months Angiographic follow-up at 9 monthsAngiographic follow-up at 9 months

TAXUS Liberte™

(N=880)(N=880)CYPER®

(N=880)(N=880)

• Significant CAD ( 50% stenosis), amenable to

stent-assisted PCI

• Silent ischemia, stable angina, and ACS (unstable

angina, NSTEMI)

Major Inclusion Criteria

• Severe LV dysfunction (EF < 25%) or Cardiogenic Shock

• STEMI requiring primary PCI

• Organ damage (Creatinine 3.0 mg/dl or LFT > 3 times)

• Left Main Disease

• In-stent restenosis of DES

• Limited life expectancy < 1 year

Major Exclusion Criteria

Primary Study EndpointPrimary Study Endpoint

• The composite clinical outcome of - Death from any cause - Myocardial infarction (MI) - Ischemia-driven target-vessel revascularization (TVR)

at 12 months after the index procedure.

Study EndpointsStudy Endpoints

• Secondary Endpoint : Death (all-cause or cardiac) : MI : Composite of death or MI : TVR (all- and ischemia-driven) : TLR (all- and ischemia-driven) : Composite of death, MI, ischemia-driven TLR : Stent thrombosis by ARC definition : Late loss in both in-stent and in-segment at 9 months : Restenosis in both in-stent and in-segment at 9 months : Procedural success rate

• Death was classified to cardiac vs. noncardiac

• MI: a new pathologic Q-wave or CK-MB > 3 times upper limit of the normal.

• TLR: any revascularization for a stenosis within the stent and adjacent 5-mm border.

• TVR: any revascularization for a stenosis at target vessel.

• Ischemia-driven: (1) >50% stenosis with ischemic signs or Sx. or

(2) >70% stenosis even without ischemic signs or Sx.

• Stent thrombosis by the ARC criteria:

(1) Definite, probable, or possible.

(2) Acute, subacute, late, or very late.

• Procedural success: final diameter stenosis <30% without in-hospital death, Q-wave MI, or urgent revascularization of the target vessel.

Outcome Definitions

Stenting ProcedureStenting Procedure

• Mixture of DES is not permitted by the protocol.

• If the patients have multiple lesions, all the lesions should be covered with the assigned study stent.

• If the assigned stent still fails to reach the lesion despite proper pre-dilation, another type of stent (either DES or BMS) may be considered.

• If the non-target vessel is too large (>4.5mm) to be stented with allocated DES, bare-metal stent can be accepted.

• Complete lesion coverage is recommended

Antiplatelet RegimenAntiplatelet Regimen

Pre-Procedure

• Aspirin (≥ 100mg)

• Clopidogrel (loading dose) : 300 or 600 mg

During Procedure

• Heparin: IV bolus + boluses to maintain ACT > 250 s

• GP IIb/IIIa inhibitors: at physician’s discretion

After Discharge

• Aspirin: 100-325 mg /day indefinitely

• Clopidogrel: 75 mg once daily for ≥ at least 12 months

Clinical Follow-up Clinical Follow-up

Clinical Follow-up

• 1, 4, 9, and 12 months

Angiographic Follow-up

• 9 (±2) months

• All patients were asked to return for an angiographic follow-up.

ZEST TrialZEST Trial - ParticipantsZEST TrialZEST Trial - Participants

1. Asan Medical Center, Seoul2. Yonsei University Medical Center, Seoul

3. Catholic Medical Center, Seoul4. Seoul National University Hospital, Seoul

5. Ajou University Hospital, Suwon6. Chonnam National University Hospital, Gwangju

7. Chungnam National University Hospital, Daejeon8. NHIC Ilsan Hospital, Ilsan9. Keimyung University Dongsan Medical Center, Daegu

10. Chonbuk National University Hospital, Jeonju11. Asan Medical Center, GangNeung12. Ulsan University Hospital, Ulsan13. Soonchunhyang University Bucheon Hospital, Bucheon14. Hallym University Sacred Heart Hospital, PyeongChon15. Daegu Catholic University Medical Center, Daegu16. Pusan Natioanal University Hospital, Pusan17. Kyungpook National University Hospital, Daegu18. Yonsei University Wonju Christian Hospital, Wonju

19. Korea University Hospital, Seoul

“19 Centers in Korea”Seung-Jung Park,

Yangsoo Jang,

Ki Bae Seung,

Hyo-Soo Kim,

Seung-Jae Tahk,

Myung Ho Jeong,

In-Whan Seong,

Joo-Young Yang,

Seung-Ho Hur,

Jae-Gun Chae,

Sang-Sig Cheong,

Sang-Gon Lee,

Nae-Hee Lee,

Young-Jin Choi,

Taeg Jong Hong,

Kee-Sik Kim,

Hun Sik Park, MD

Junghan Yoon, MD

Do-Sun Lim, MD

ResultsResults

Baseline Characteristics

Patients ZES(n=883)

SES(n=878)

PES (n=884)

P value

Age (yr) 62±9 62±10 62±10 0.80

Male sex 586 (66) 591 (67) 582 (66) 0.80

Body mass index 25±3 25±3 25±3 0.88

Diabetes mellitus

Any diabetes 268 (30) 247 (28) 245 (28) 0.42

Requiring insulin 32 (4) 33 (4) 36 (4) 0.88

Hypertension 552 (63) 517 (59) 540 (61) 0.29

Hyperlipidemia 466 (53) 451 (51) 446 (51) 0.62

Current smoker 236 (27) 256 (29) 243 (28) 0.51

Family history of CAD 48 (5) 44 (5) 52 (6) 0.72

n (%)

Baseline CharacteristicsPatients ZES

(n=883)SES

(n=878)PES

(n=884)P

value

Previous PCI 75 (9) 82 (9) 83 (9) 0.76

Previous CABG 6 (1) 6 (1) 5 (1) 0.94

Previous MI 30 (3) 39 (4) 41 (5) 0.37

Previous CHF 9 (1) 4 (1) 7 (1) 0.39

Chronic lung disease 13 (2) 8 (1) 26 (3) 0.004

Cerebrovascular disease 65 (7) 55 (6) 53 (6) 0.47

Peripheral vascular disease 15 (2) 21 (2) 17 (2) 0.57

Renal insufficiency 7 (1) 7 (1) 6 (1) 0.95

Multi-vessel disease 414 (47) 430 (49) 410 (46) 0.51

Ejection fraction (%) 61±8 61±8 61±8 0.59

n (%)

Baseline Characteristics

Patients ZES(n=883)

SES(n=878)

PES (n=884)

P value

Clinical indication (%) 0.73

Silent ischemia 48 (5) 44 (5) 56 (6)

Chronic stable angina 348 (39) 343 (39) 343 (39)

Unstable angina 410 (46) 424 (48) 403 (46)

NSTEMI 77 (9) 67 (8) 82 (9)

Electrocardiographic findings

0.99

Sinus rhythm 850 (96) 849 (97) 854 (97)

Atrial fibrillation 21 (2) 18 (2) 17 (2)

Other 12 (1) 11 (1) 13 (1)

n (%)

Lesions ZES(n=1190)

SES(n=1218)

PES (n=1205)

P value

Location 0.39

LAD 622 (52) 645 (53) 611 (51)

LCX 252 (21) 225 (19) 253 (21)

RCA 316 (27) 348 (29) 340 (28)

Coronary graft 0 0 1 (0.1)

ACC-AHA B2 or C type 858 (72) 921 (76) 895 (74) 0.14

Total occlusion 68 (6) 76 (6) 96 (8) 0.07

Thrombus-containing 32 (3) 37 (3) 38 (3) 0.78

Bifurcation lesion 181 (15) 151 (12) 168 (14) 0.14

Ostial lesion 85 (7) 72 (6) 82 (7) 0.45

Restenotic lesion 5 (0.4) 12 (1) 13 (1) 0.16

Lesion Characteristics

n (%)

Lesions ZES(n=1190)

SES(n=1218)

PES (n=1205)

P value

Calcification 0.76

None or mild 1129 (95) 1145 (94) 1132 (94)

Moderate 40 (3) 43 (4) 46 (4)

Severe 21 (2) 30 (3) 27 (2)

Lesion length 0.09

<10 mm 73 (6) 71 (6) 61 (5)

10-20 mm 466 (39) 444 (37) 504 (42)

>20 mm 651 (55) 703 (58) 640 (53)

Lesion Characteristics

n (%)

Lesions ZES(n=1190)

SES(n=1218)

PES (n=1205)

P value

No. of stents per lesion 1.2±0.4 1.2±0.4 1.2±0.4 0.35

No. of stents per patient 1.6±0.9 1.6±0.9 1.6±0.9 0.92

Length of stents per lesion 27.9±13.1 28.9±13.5 28.9±14.3 0.12

Length of stents per patients 39.7±26.8 38.3±24.3 38.9±25.2 0.45

Maximal stent diameter 3.4±0.7 3.4±0.7 3.5±0.6 0.03

Maximal pressure 16.3±4.2 16.3±4.1 16.2±4.2 0.95

Direct stenting 84 (7) 109 (9) 89 (7) 0.24

Use of IVUS 488 (41) 514 (42) 491 (41) 0.62

Use of glycoprotein IIb-IIIa inhibitors 19 (2) 15 (2) 14 (2) 0.64

Procedural Characteristics

Patients ZES(n=883)

SES(n=878)

PES (n=884)

P value

Aspirin 882 (99.9) 873 (99.4) 880 (99.5) 0.27

Clopidogrel 876 (99.2) 874 (99.5) 881 (99.7) 0.39

Cilostazol 251 (28.4) 230 (26.2) 244 (27.6) 0.54

Warfarin 3 (0.3) 7 (0.8) 6 (0.7) 0.44

Statin 698 (79.0) 720 (82.0) 715 (80.9) 0.29

ACE inhibitor 343 (38.8) 312 (35.5) 315 (35.6) 0.26

ARB 235 (26.6) 222 (25.3) 242 (27.4) 0.60

ß-blocker 581 (65.8) 562 (64.0) 594 (67.2) 0.37

Calcium channel blocker 460 (52.1) 481 (54.8) 439 (49.7) 0.10

Discharge Medications

0 30 60 90 120 150 180 210 240 270 300 330 3600

5

10

15

Sirolimus stent

Zotarolimus stent

Paclitaxel stent

Days after Initial Procedure

Cu

mu

lati

ve

In

cid

en

ce

of

Pri

mar

y E

nd

po

int

(%)

Zotarolimus- vs. Sirolimus-stent; P for non-inferiority= 0.01

No. at RiskZotarolimus stent 883 827 816 790 782Sirolimus stent 878 816 813 802 792 Paclitaxel stent 884 821 808 763 745

Zotarolimus- vs. Paclitaxel-stent; P for superiority=0.01

Background: ZEST at 1-Year Primary Endpoint

Park et al. JACC2010

14.1%

10.2%

8.3%

Overall P=0.31*ZES vs. SES = 0.32*ZES vs. PES = 0.11 SES vs. PES =0.56

Death or MI at 12 month

7.6%

5.8%

6.9%

15

5

0 30 60 90 120 150 180 210 240 270 300 330 360

Follow-Up (Days)

Cu

mu

lati

ve In

cid

ence

(%

)

ZES

SESPES

No. at RiskZES 883 828 824 820 820 SES 878 817 814 811 804PES 884 821 815 808 803

Park et al. JACC2010

0.8%0.7%

0%

Overall P = 0.02*ZES vs. SES = 0.03*ZES vs. PES > 0.99 SES vs. PES = 0.02

Stent thrombosis at 12 month: ARC Definite or Probable Criteria

Follow-Up (Days)

Cu

mu

lati

ve In

cid

ence

(%

)3

2

0 30 60 90 120 150 180 210 240 270 300 330 3600

1

ZES

SESPES

No. at RiskZES 883 869 866 861 861 SES 878 869 867 863 857PES 884 875 868 859 853

Park et al. JACC2010

Background: ZEST at 1-Year Angiographic Outcomes

Background: ZEST at 1-Year Angiographic Outcomes

0.0

0.1

0.2

0.3

0.4

0.5In-segment

late loss

0

24

68

10

1214

1618

20

0.30 ±0.52

0.11 ±0.35

0.32 ±0.51

ZES SES

In-segment restenosis

12.1% 2.4% 12.4%

PES

P<0.001P<0.001

Park et al. JACC2010

Conclusion: ZEST at 1 YearConclusion: ZEST at 1 Year

• In this large-scale, practical RCT, the zotarolimus-eluting stent compared to the sirolimus-eluting and the paclitaxel-eluting stent resulted in:

ZES was noninferior to SES and was superior to PES in the composite endpoint of death, MI, and ischemia-driven TVR at 12 months.

Rate of death or MI at 1-year was similar among the 3 groups.

SES is associated with lowest angiographic restenosis, with lowest need for TLR, and with the lowest risk of stent thrombosis among the tested 3 type of DES.

Park et al. JACC2010